In this project we are coupling genetic study with epidemiologic, immunologic, serologic and neurochemical studies in selected families and twin pairs with disorders due to multiple factors such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Genetic study of 41 monozygotic twin pairs and 19 dizygotic twin pairs, selected on the basis of at least one member being diagnosed as having Parkinson's disease, revealed only one monozygotic twin pair and none of the dizygotic group definitely concordant for the disease. Although the unaffected co-twin in each case remains at risk, this very low concordance suggests that neither typical environmental nor genetic factors are critical determinants. Data on smoking from three of our studies support an earlier impression that there is a decreased risk for Parkinson's disease in smokers. Analysis of clinical and psychological observation, and interview data on 21 MZ twin pairs discordant for Parkinson's disease indicates life-long differences in personality are present in affected versus unaffected twins, as our preliminary study suggested. These observations are consistent with the existence of a protective factor, present in limited amount, supplied unequally to the twins in utero so that one twin is at less risk and the other at greater risk for Parkinson's disease. An hereditary leukoencephalopathy simulating MS with onset at about age 35 is under study in a kindred with over 20 affected. Derangement of the autonomic nervous system is often seen early in the course and when recognized, serves to distinguish this single gene disorder from multiple sclerosis clinically. Computerized tomographic scan changes are dramatic.